A number of effective anticonvulsants including the compound 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate, also known as topiramate, have been disclosed in U.S. Pat. No. 4,513,006. Topiramate is useful in the treatment of human epilepsy in that it is effective as adjunctive therapy or as monotherapy in treating simple and complex partial seizures and secondarily generalized seizures (E. Faught et. al., Epilepsia 36 (S4) 33, 1995; S. K. Sachdeo, et al., Epilepsia 36 (S4) 33, 1995). Topiramate is currently marketed for the treatment of simple and complex partial seizure epilepsy with or without secondary generalized seizures.
Recent preclinical studies on topiramate have revealed previously unrecognized pharmacological properties which suggest that topiramate is effective in treating some other disorders. One of these is neuropathic pain. Neuropathic pain remains one of the “frontiers” of pain management. There is a significant unmet need for efficacious and tolerable pharmacotherapy, making neuropathic pain an area of intense research interest. The term “neuropathic pain” is applied to any acute or chronic pain syndrome in which the sustaining mechanism for the pain is believed to involve abnormal transmission (peripheral) or processing (central) of somatosensory input. U.S. Pat. No. 5,760,007 discloses topiramate as useful for the treatment of neuropathic pain.
A class of analgesic cycloalkanol-substituted phenol esters having a basic amine group in the cycloalkylring, are disclosed in U.S. Pat. No. 3,652,589. Among these is the compound (1R,2R or 1S,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexan-1-ol, generically designated as tramadol, which is specifically disclosed therein. Tramadol typically is used as the hydrochloride salt form.
A series of articles pertaining to the pharmacology, toxicology and clinical studies of tramadol hydrochloride are found in Arzneim. Forsch., (Drug Res.), 1978, 28(1), 114. The Abstracts of the VI th World Congress on Pain, Apr. 1-6 (1990), disclose that tramadol hydrochloride is an orally active pure agonist opioid analgesic. However, clinical experience indicates that tramadol hydrochloride lacks many of the typical side effects of opioid agonists. Tramadol hydrochloride's ‘atypical’ combination of non-opioid and opioid activity makes tramadol a very unique drug. Tramadol hydrochloride is currently marketed as an analgesic.
Opioids have for many years been used as analgesics to treat severe pain. They, however, produce undesirable side effects such as respiratory depression, constipation, tolerance and abuse liability, and, as a result, cannot always be given repeatedly or at high doses.
To reduce the side effect problems, opioids have been combined with other drugs, including non-opioid analgesic agents, which lower the amount of opioid needed to produce an equivalent degree of analgesia. It has been claimed that some of these combination products also have the advantage of requiring less of each ingredient while producing a synergistic analgesic effect.
As an analgesic, tramadol hydrochloride has been combined with both opioid and non-opioid analgesic drugs. Such compositions have exhibited synergistic effects in treating pain while using less of each ingredient to produce an equivalent degree of analgesia. Specifically, U.S. Pat. No. 5,516,803 discloses the composition of tramadol hydrochloride and a NSAID, particularly ibuprofen. U.S. Pat. No. 5,468,744 discloses tramadol hydrochloride plus any of oxycodone, codeine or hydrocodone and U.S. Pat. No. 5,336,691 discloses tramadol hydrochloride in combination with acetaminophen.
WO-01/13904 is concerned with a pharmaceutical composition comprising a combination of a tramadol material and an anticonvulsant drug and to the pharmacological use of the composition in treating conditions of pain and neurologic or psychiatric disorders. The composition produces a combination product having improved properties, requiring less of each ingredient and producing a synergistic effect.
WO-01/13904 further discloses that in animal studies using the Chung model of post-nerve constriction injury, both tramadol hydrochloride and topiramate are significantly active and reach 100% MPE (Maximum Possible Effect) as the dose is escalated. When topiramate and tramadol hydrochloride are co-administered in this model the ED50 of both drugs is dramatically reduced, suggesting synergy of analgesic effect. The degree of synergy varies across ratios in this model with those ratios in which tramadol hydrochloride predominates displaying the greatest synergy.
Compositions including combinations of topiramate and tramadol hydrochloride have been found to be relatively unstable, in particular due to the instability of topiramate. It is therefore a desirable goal to provide combination formulations of topiramate and tramadol hydrochloride that are stable.
Moreover, the half lives of topiramate and tramadol are largely different in that tramadol's half life is relatively short while that of topiramate is relatively longer. Plasma levels of tramadol therefore will sink more rapidly below effectivity thresholds than those of topiramate, which is undesirable because there is a need to keep the blood plasma levels of both active ingredients at a sufficient level, in particular during a relatively long period of time. Therefore there is a need to provide pharmaceutical compositions that release both topiramate and tramadol at a sufficient level, during a sufficiently long period of time. The present invention provides an adduct of topiramate and tramadol, which allows the preparation of pharmaceutical compositions that meet this need.